The present invention relates to the field of pharmacology and, more particularly, to heterocyclic compounds and their use in the treatment of sexual disorders such as decreased libido, orgasm disorder and erectile dysfunction.
Erectile dysfunction (ED), the most common sexual arousal disorder, involves partial or complete failure to attain or maintain a penile erection adequately for intercourse. Erectile dysfunction is a very common problem, affecting from about 40 to 60 percents of men at some time in their life, and about 52 percents of men between 40 and 70 years old.
Penile erection occurs when blood vessels in the penis, particularly in the corpus cavernosum, become filled with large volumes of blood, causing an enlargement and stiffening of the organ. In response to stimuli from the cerebral cortex and/or the parasympathetic nervous system, nitric oxide is released in penile arteries. Nitric oxide causes the smooth muscle in arteries to relax by activating guanylyl cyclase, increasing the concentration of cyclic guanosine monophosphate (cGMP), which activates protein kinase G. The relaxation of the arterial smooth muscle causes the arteries to expand, increasing the volume of blood flowing through the arteries. The increased volume of blood entering the penis leads to an erection. In women, clitoral erection is caused by an analogous mechanism.
The biological effect of nitric oxide is limited by phosphodiesterases (PDEs) which hydrolyze cGMP. Inhibition of PDEs increases the levels of cGMP induced by nitric oxide, thereby magnifying the effects of nitric oxide. Eleven families of phosphodiesterase are known, and their effects depend on their distribution in the body and on their relative specificity for cGMP and/or cyclic adenosine monophosphate (cAMP). cAMP is a compound related to cGMP, which is known to affect many biological processes, including regulation of metabolism and blood flow, by activating protein kinase A.
For instance, PDE3 and PDE4 selectively hydrolyze cAMP (Beavo, 1998). However, while inhibition of these enzymes may prevent erectile dysfunction (Steers, 2002), it also leads to serious adverse side effects, such as enhanced myocardial contraction and heart rate and depression of systemic blood pressure (Andrews and Cowley, 1993).
In contrast, PDE5 is specific for cGMP, which affects fewer biological processes than does cAMP, and is located prominently in the penis. PDE5, first purified and characterized from rat (Francis and Corbin, 1988), is very abundant in vascular smooth muscle cells and appears to play a significant role in modulating smooth muscle tone in general and penile corpus cavernosal smooth muscle tone in particular (Beavo, 1998; Moreland and Goldstein, 1995). Selective inhibitors of PDE5 have therefore been suggested for inducing penile (and clitoral) erection by raising cGMP levels (Terret et al., 1996). It should be noted, however, that elevating cGMP levels would fail to lead to an erection in the absence of production of cGMP in response to a stimulus.
The principal currently available drugs belonging to the PDE5 inhibitors family are tadalafil (Clalis™), vardenafil (Levitra™) and sildenafil (Viagra™), the most famous one being Viagra™ (sildenafil).
Sildenafil was the first selective orally-administered PDE5 inhibitor for treating erectile dysfunction. Vardenafil has a structure very similar to that of sildenafil. Tadalafil contains a methylenedioxyphenyl moiety and is structurally different (Corbin et al., 2002). The chemical structures of these compounds are presented in Scheme 1 below.
Patients suffering from erectile dysfunction generally respond well to medications of the phosphodiesterase type 5 (PDE5) inhibitors family, with approximately 80% success rates (Evans et al., 1980; Hyttel, 1982).
In addition to erectile dysfunction patients, it has been found that many consumers of PDE5 inhibitors are physically healthy men, with no pathological sexual problems, who are aiming to improve the quality of their sexual performance by enhancing extent and duration of erection.
Although sildenafil is considered a selective inhibitor of PDE5, it has long been recognized that it effects on other body organs and hence its use is associated with several adverse side effects such as nausea, headache, and cutaneous flushing. These clinically significant adverse effects are thought to be due to nonspecific inhibition of other PDEs exhibited by this compound (Beavo, 1998; Moreland and Goldstein, 1995).

It has therefore been recognized that an improved, second generation of PDE5 inhibitors would be one with greater potency and specificity for PDE5, resulting in potentially fewer PDE-associated side effects and greater efficacy in the treatment of erectile dysfunction. To this end, several types of nitrogen-containing heterocyclic scaffolds such as quinazoline (Takase et al., 1994; Takase et al., 1994), pyrazolo-pyrimidine (Terret et al., 1993; Dumaitre, Dodic, 1996), isoquinoline (Ukida, 2001), phthalazine (Watanabe, 2000), and naphthalene (Ukida, 1999) derivatives have been synthesized. Some of these compounds have been identified as being potent and selective PDE5 inhibitors (Rotella D P, 2002)
In addition to PDE5, experimental data indicate that several neurotransmitters and neuropeptides in the central nervous system are involved in the control of penile erection and sexual behavior, one such prominent neurotransmitter being dopamine (Melis and Argiolas, 1995; Andersson, 2001). In contrast to PDE5 inhibition, which directly affects the blood vessels in the penis, dopamine is involved in the regulation of penile activity by the central nervous system.
Dopamine is one of the key mediators in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward and hormonal regulation. Dopamine receptors in mammalian tissues have been classified as D1-like (D1 and D5) and D2-like (D2, D3, and D4) (Missale, 1998). It has been shown that several dopamine receptor agonists such as apomorphine, quinpirole, quinelorane, and (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) induce penile erection after systemic administration in mammals (Melis and Argiolas, 1995).
Recent demonstration that apomorphine can facilitate penile erection in erectile dysfunction patients has introduced a new approach to pharmacological correction of erectile dysfunction. It is believed that apomorphine induces penile erection by activating the D4 receptor, although other dopamine receptors may also be involved (Brioni et al., 2004). However, apomorphine is classified as a nonselective agonist because it activates all of the dopamine receptor subtypes (Missale, 1998). It is believed that such non-selectivity is associated with the known emetic action that substantially restricts the practical application of apomorphine. It has therefore been considered desirable to obtain selective D4 agonists.
One selective D4 agonist that was found active in penile erection is ABT-724 (2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole) (Brioni et al., 2004). Methods of using ABT-724 and related compounds in the treatment of various sexual dysfunctions are disclosed in U.S. Pat. Nos. 7,022,728 and 6,960,589, to Cowart et al. The chemical structures of apomorphine and ABT-724 are presented in Scheme 2 below.

Other highly selective dopamine receptor D4 agonists have also been developed. These include, for example, PD-168077 and PIP3EA (Melis et al., 2006), A-412997 (Moreland et al., 2005) and A-381393 (Nakane et al., 2005). These compounds are structurally similar to ABT-724, comprising substituted phenyl groups instead of the pyridine group in ABT-724. In addition, PIP3EA comprises 2-imidazo[1,2-a]pyridine instead of the benzoimidazole in ABT-724, A-412997 and PD-168077 comprise a monocyclic aryl group linked by an amide bond instead of benzoimidazole, and A-412997 comprises piperidine instead of piperazine.
In view of the significance of certain types of dopamine receptors in the control of sexual behavior and penile erection, the discovery of ABT-724 (Brioni et al, 2004; Cowart et al, 2004) and development of other highly selective dopamine receptor D4 agonists (Moreland, 2001) have provided a new strategy for the treatment of ED. A further potential advantage for the use of dopamine receptor agonists is the ability of dopamine receptor agonists, selective D4 agonists in particular, to treat a range of sexual disorders.
An example of another type of sexual disorder is the orgasm disorder, in which orgasm and/or ejaculation are absent or delayed to a degree in which sexual satisfaction is significantly reduced, even in the presence of an adequate erection. One common cause of orgasm disorder is selective serotonin reuptake inhibitor (SSRI) therapy.
Dopamine has been found to regulate ejaculation via D2-like receptors (Wolters & Hellstrom, 2006). Bupropion and amantadine, which stimulate dopamine pathways, have been reported to reverse orgasm disorders (Modell et al., 2000; Balon, 1996), and SSRI-induced orgasm disorders are suspected to be induced by inhibition of dopamine pathways (Alcantara, 1999). PDE5 inhibitors have also been found to reverse SSRI-induced orgasm disorders (Ashton, 2004; Damis et al., 1999).
Another example of a type of sexual disorder is decreased libido, or sexual desire disorder, which is often attributed to aging, psychological disorders such as depression, and medications such as SSRIs.
Dopamine release plays an important role in sexual desire, apparently as part of the general role of dopamine in providing motivation for rewarding activities (Giuliano and Allard, 2001). Consequently, dopamine antagonists tend to reduce sexual desire (Stimmel and Gutierrez, 2006). The D4 receptor in particular has been linked to sexual desire, as well as sexual arousal and function (Ben-Zion et al., 2006).
Thus, while the art teaches some PDE5 inhibitors that are useful in the treatment of erectile dysfunction, the use of these compounds is limited by the adverse side effects associated therewith and is further limited to by addressing only a single biological pathway that leads to erectile dysfunction. The art further teaches agents that act via the dopamine pathway, for treating erectile dysfunction and related disorders. The clinical effect of these agents, however, has not been practiced yet.
There is thus a widely recognized need for, and it would be highly advantageous to have novel compounds for treating sexual disorders, devoid of the above limitations.